Glucocorticoid treatment influences prostate cancer cell growth and the tumor microenvironment via altered glucocorticoid receptor signaling in prostate fibroblasts

Despite significant therapeutic advances in recent years, treatment of metastatic prostate cancer (PCa) remains palliative, owing to the inevitable occurrence of drug resistance. There is increasing evidence that epithelial glucocorticoid receptor (GR) signaling and changes in the tumor-microenviron...

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Bibliographic Details
Published in:Oncogene 2024-01, Vol.43 (4), p.235-247
Main Authors: Eigentler, Andrea, Handle, Florian, Schanung, Silvia, Degen, Antonia, Hackl, Hubert, Erb, Holger H H, Fotakis, Georgios, Hoefer, Julia, Ploner, Christian, Jöhrer, Karin, Heidegger, Isabel, Pircher, Andreas, Klotz, Werner, Herold, Manfred, Schäfer, Georg, Culig, Zoran, Puhr, Martin
Format: Article
Language:English
Subjects:
Androgen receptors
Cancer-Associated Fibroblasts - metabolism
Cell culture
Cell growth
Cell Line, Tumor
Drug resistance
Extracellular matrix
Fibroblasts
Fibroblasts - metabolism
Gene expression
Glucocorticoid receptors
Glucocorticoids
Glucocorticoids - metabolism
Glucocorticoids - pharmacology
Glucocorticoids - therapeutic use
Humans
Male
Metastases
Metastasis
mRNA
Prostate - pathology
Prostate cancer
Prostatectomy
Prostatic Neoplasms - drug therapy
Prostatic Neoplasms - genetics
Prostatic Neoplasms - metabolism
Protein expression
Receptors, Glucocorticoid - genetics
Receptors, Glucocorticoid - metabolism
Secretome
Tumor Microenvironment
Tumors
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Summary:Despite significant therapeutic advances in recent years, treatment of metastatic prostate cancer (PCa) remains palliative, owing to the inevitable occurrence of drug resistance. There is increasing evidence that epithelial glucocorticoid receptor (GR) signaling and changes in the tumor-microenvironment (TME) play important roles in this process. Since glucocorticoids (GCs) are used as concomitant medications in the course of PCa treatment, it is essential to investigate the impact of GCs on stromal GR signaling in the TME. Therefore, general GR mRNA and protein expression was assessed in radical prostatectomy specimens and metastatic lesions. Elevated stromal GR signaling after GC treatment resulted in altered GR-target gene, soluble protein expression, and in a morphology change of immortalized and primary isolated cancer-associated fibroblasts (CAFs). Subsequently, these changes affected proliferation, colony formation, and 3D-spheroid growth of multiple epithelial PCa cell models. Altered expression of extra-cellular matrix (ECM) and adhesion-related proteins led to an ECM remodeling. Notably, androgen receptor pathway inhibitor treatments did not affect CAF viability. Our findings demonstrate that GC-mediated elevated GR signaling has a major impact on the CAF secretome and the ECM architecture. GC-treated fibroblasts significantly influence epithelial tumor cell growth and must be considered in future therapeutic strategies.
ISSN:0950-9232
1476-5594
1476-5594
DOI:10.1038/s41388-023-02901-5